Abstract The candidate, David P. Sparling, MD, PhD, proposes a Clinical Scientist Development Award project as a means to achieve his goal of becoming an independent physician scientist studying the regulation of adipose tissue and inflammation in obesity and Type 2 diabetes mellitus (T2DM). While much effort has been put into understanding the role of inflammatory cells, e.g. macrophages and T cells, in the progression of adipose tissue insulin resistance, there should also be a focus on the cell likely originating those inflammatory signals?namely, the adipocyte. A variety of signaling events likely occur during the inflammatory processes in excessive adiposity, and a novel tool has been implicated to study these processes: the ?-secretase enzyme complex. Signaling cascades regulating both adipose differentiation and insulin sensitivity cascades utilize ?-secretase, and it plays a role in several immune signaling cascades in other cell types. However, the function of??-secretase in adipocyte-initiated inflammatory signaling is unknown. Dr. Sparling proposes that ?-secretase blockade could be a tool to identify novel cascades and signaling functions in adipocyte inflammation. Preliminary data has suggested that adipocyte-specific blockade of ?-secretase alters the inflammatory milieu of lean and obese adipose tissue. Dr. Sparling hypothesizes that ?-secretase is integral to adipocyte-initiated inflammatory signaling cascades, and that this hypothesis can be tested in vitro with two specific aims. Aim 1 will determine if ?-secretase is required for adipocyte-initiated macrophage recruitment and activation, and Aim 2 will determine if the immunoreceptor TREM2 in adipocytes is regulated in a ?-secretase dependent manner. Dr. Sparling will first identify the role of adipocyte ?-secretase in recruitment and activation of macrophages. He will identify changes in established inflammatory cytokines MCP1 and IL6 secreted by adipocytes following ?-secretase inhibition. He will also explore novel targets of ?-secretase regulated intramembrane proteolysis that play a role in adipocyte inflammation. He will then examine the alterations in TREM2 signaling following ?-secretase inhibition. TREM2 is a known ?-secretase target in immune cells, and can regulate adipose function. He will determine if ?-secretase inhibition alters TREM2 protein-protein interactions and downstream signaling in adipocytes. In the long term, this work seeks to establish how adipocytes regulate inflammatory signals in the progression of obesity to T2DM. Dr. Sparling has shown a lasting commitment to basic research and its possible translation to clinical practice. His dissertation at the University of Oklahoma was on the transcriptional regulatory mechanisms of the insulin-responsive glucose transporter GLUT4. After pediatrics residency at Columbia University he completed a fellowship in pediatric endocrinology, studying the role of the Notch cascade in developed adipose tissue. This work was funded by the Endocrine Fellows Foundation and the Pediatric Endocrine Society, and resulted in a first author publication. He accepted his position as an Assistant Professor at the University of Oklahoma Health Sciences Center, Department of Pediatrics, in the Section of Pediatric Diabetes and Endocrinology, where he now has protected time to begin his research career. The basis of Dr. Sparling's work has been in adipose biology, but has now expanded to focus on inflammatory signaling. As such, training gaps for Dr. Sparling have been identified: his understanding of immune cell function and inflammatory regulators, as well as a need for better understanding of appropriate techniques in advanced data analysis. To reach his goal as an independent clinician scientist studying adipose inflammation, these gaps must be addressed. The K08 award provides an excellent means to achieve these goals. During the award Dr. Sparling will: 1) Expand his understanding of the immune system and inflammatory signaling cascades. This will primarily be through instruction and training by his mentor, Dr. Mary Beth Humphrey, chair of the Division of Rheumatology, Immunology, and Allergy in the Department of Medicine at OUHSC. He will also attend graduate didactic courses in immunology, as well as immunology research conferences on campus. 2) Acquire advanced training in statistical analysis through additional statistics courses offered through the Department of Biostatistics and Epidemiology in the College of Public Health at OUHSC. Obesity continues to plague both pediatric and adult populations, and inflammation can play a role in insulin resistance. What is not fully known is what degree inflammation is initiated directly by the adipocyte, and how that signaling evolves in the progression to T2DM. The goal of this award is to develop the skills to examine how inflammatory signals effect cross-talk between adipocytes and the immune system. The environment at the University of Oklahoma is well suited for this work, with mentors, collaborators, and resources all available to successfully complete this project. The training afforded by this award will prepare Dr. Sparling to seek ongoing extramural funding to continue to contribute to the field of diabetes and endocrinology.